CD4+ T-helper (Th) cells of the Th1 phenotype are critical for host protection against tumors (Tatsumi, et al., 2002, J Exp Med 196:619-628) and infections (Holland, 2007, Immunol Res 38:342-346) but must be tightly regulated to promote self-tolerance (Lu, et al., 2010, Cell 142:914-929) and to limit alloimmunity during transplantation therapy (Mariotti et al., 2008, Blood 112:4765-4775). Th1 cells are amenable to regulation by multiple mechanisms, such as FAS-mediated antigen-induced cell death (Ramsdell, et al., 1994, Int Immunol 6:1545-1553) and regulatory T (Treg) cell inhibition (Lu, et al., 2010, Cell 142:914-929). One such mechanism of regulation is differentiation ‘plasticity’ among Th cell subsets, with functional subset inter-conversion depending on the cytokine micro-environment (O'Shea and Paul, 2010, Science 327:1098-1102). Such plasticity, which has primarily been studied in murine T cells, is most prevalent for Treg and Th17 subsets: Treg cells can morph into Th17 cells upon IL-1 or IL-6 receptor signaling and subsequent STAT3 activation (Koenen, et al., 2008, Blood 112:2340-2352; Yang, et al., 2008, Immunity 29:44-56), and Th17 cells can switch into a Th1 phenotype under the influence of IL-12 signaling and subsequent STAT4 activation (Mukasa, et al., 2010, Immunity 32:616-627).
In contrast, the Th1/Th2 subsets are relatively fixed in their differentiation status (O'Shea and Paul, 2010, Science 327:1098-1102); nonetheless, counter-regulatory cytokines have long been known to promote Th1 to Th2 conversion (Sher, et al., 1991, J Immunol 147:2713-2716) or Th2 to Th1 shifts (Fiorentino, et al., 1989, J Exp Med 170:2081-2095) by activating specific transcription factors. Although STAT4 activation is required for initial Th1 polarization (Mullen, et al., 2001, Science 292:1907-1910), STAT1 activation through IFN-α or IFN-γ receptor signaling appears to be the major contributor to Th1 cell stability through promotion of TBET transcription factor expression (Lighvani, et al., 2001, Proc Natl Acad Sci USA 98:15137-15142; Afkarian, et al., 2002, Nat Immunol 3:549-557).
Recently, the PD1/PDL1 pathway has emerged as a central player in immune regulation (Francisco, et al., 2010, Immunol Rev 236:219-242). Cancer cells that express PDL1 (also known as B7-H1) promote tumor progression through inhibition of PD1-expressing immune effectors (Ohigashi, et al., 2005, Clin Cancer Res 11:2947-2953); in addition, PDL1 modulates cell-mediated immunity in the infectious disease setting (Mueller, et al., 2010, J Clin Invest 120:2508-2515). Furthermore, allogeneic effector T cell responses are susceptible to PD1 pathway modulation, as evidenced in models of graft-versus-host disease (GVHD) (Blazar, et al, 2003, J Immunol 171:1272-1277) and graft rejection (Lee, et al., 2003, J Immunol 171:6929-6935).
PD1/PDL1 interactions have been characterized previously to inhibit T cell receptor (TCR) signaling by recruiting the SHP-1 and SHP-2 (SHP1/2) phosphatases, which interfere with TCR signaling (Chemnitz, et al., 2004, J Immunol 173:945-954) and induce a TCR stop signal that limits T cell interactions with dendritic cells (DC) (Fife, et al., 2009, Nat Immunol 10:1185-1192). Such immune modulation mechanisms are not specific for Th1 cells: For example, PD1 activation inhibits the suppressor function of Treg cells (Franceschini, et al., 2009, J Clin Invest 119:551-564) and impairs monocyte immunity (Ma et al., 2011 Immunology 132(3):421-31) in humans infected with hepatitis C. In addition to such direct mechanisms of T cell anergy, PDL1 also indirectly modulates T cells by inducing plasmacytoid DCs, which increase Treg cell numbers and result in Treg cell suppression of anti-tumor responses in a PDL1-dependent manner (Sharma et al., 2007, J Clin Invest 117:2570-2582). This DC/Treg cell biology can be bi-directional, as human PDL1-expressing Tregs condition monocytes to express PDL1 and suppress cell-mediated immunity (Amarnath, et al., 2010, PLoS Biol 8:e1000302). Furthermore, PD1 activation of naïve T cells favors inducible Treg formation by promoting phosphatase and tensin homolog (PTEN) expression and limiting downstream mTOR activation (Francisco, et al., 2009, J Exp Med 206:3015-3029).
There have been no reports in the literature to suggest that PD1/PDL1 interactions play a special role in the modulation of Th1 cell plasticity. There remains a need in the art for compositions and methods of differentiating Th1 cells. The present invention fills this need in the art.